Aldol condensation reactions are important in the production of intermediates needed to synthesize many commercially important products. The condensation of ketones to obtain aldols (β-hydroxy ketones) is a well-known reaction. Dehydration of the resulting aldol to obtain an unsaturated ketone is also known. Subsequent catalytic hydrogenation of the unsaturated ketone may be carried out to obtain the corresponding saturated higher ketone.
In an aldol condensation reaction, two aldehydes or ketones, or one of each, each having a hydrogen atom alpha to the carbonyl, react together to form a β-hydroxy-aldehyde or a β-hydroxy-ketone. Many methods have been disclosed in the art to perform aldol condensation reactions. These include two-phase liquid reactions using dilute aqueous base as the catalyst, see, for example, U.S. Pat. No. 6,232,506, U.S. Pat. Appln. No. 2002/0161264, U.S. Pat. No. 6,433,230, U.S. Pat. No. 2,200,216, U.S. Pat. No. 6,288,288; base-catalyzed, liquid phase aldol condensation reactions that include the use of a solubilizing or phase transfer agent, see, for example, U.S. Pat. Nos. 2,088,015, 2,088,016, 2,088,017, and 2,088,018; and the use of polymeric or oligomeric ethylene glycols or polyhydric alcohols as phase transfer catalysts or solvents in combination with dilute alkali metal hydroxide catalysts, see, for example, U.S. Pat. Nos. 5,055,621, and 5,663,452, and U.S. Pat. Publ. No.2002/0058846.
The β-hydroxy-aldehyde or β-hydroxy-ketone product of such aldol condensations can dehydrate to give a conjugated α,β-unsaturated aldehyde or ketone. Many methods are known in the art for dehydrating β-hydroxy-aldehydes or β-hydroxy-ketones to α,β-unsaturated aldehydes or ketones, in fair to excellent yields. These include simple heating; acid-catalyzed dehydration using mineral acids or solid acid catalysts, with or without azeotropic removal of the water of reaction, as exemplified in U.S. Pat. No. 5,583,263, U.S. Pat. No. 5,840,992, U.S. Pat. No. 5,300,654, and Kyrides, JACS, Vol 55, August, 1933, pp. 3431-3435; heating with iodine crystals, as in Powell, JACS, Vol. 46, 1924, pp. 2514-17; and base-catalyzed dehydration, as taught in Streitwieser and Heathcock, “Introduction to Organic Chemistry”, 2nd Ed., 1981, pp. 392-396.
The conditions needed for the aldol dehydration are often only a bit more vigorous than the conditions needed for the aldol condensation itself. As a result, the α,β-unsaturated ketone is often the only product obtained from the reaction, while the initial β-hydroxy ketone is not typically isolated.
In some cases, it is desirable to selectively hydrogenate the carbon-carbon double bond of the resulting α,β-unsaturated ketone to give a saturated ketone. Many catalysts and methods are known for such hydrogenation reactions, as exemplified in U.S. Pat. Nos. 5,583,263 and 5,840,992, and U.S. Pat. Appl. Nos. 2002/0128517, 2002/058846, and 2002/0169347. Alkenes react with hydrogen gas in the presence of a suitable metal catalyst, typically palladium or platinum, to yield the corresponding saturated alkane addition products. The metal catalysts are normally employed on a support or inert material, such as carbon or alumina. Commercially important products of this type include methyl amyl ketone, methyl isoamyl ketone, and methyl propyl ketone, made by the crossed condensation of acetone with n-butryaldehyde, isobutyraldehyde, or acetaldehyde, respectively.
Aldehydes are more reactive, in general, than are ketones in base-catalyzed aldol condensations, because of the greater ease of enolate ion formation of an aldehyde. As such, in a crossed condensation of a ketone with an aldehyde to produce a desired β-hydroxyketone, the self-condensation of the aldehyde typically occurs in substantial quantities to produce an undesired β-hydroxyaldehyde by-product. Further, unhindered aldehydes, i.e., straight-chain aldehydes such as acetaldehyde, propionaldehyde, n-butyraldehyde, and n-pentanal, are more reactive toward self-condensation than hindered aldehydes, i.e., branched aldehydes such as 2-methyl-propanal and 3-methyl-butanal.
It is understood that the rate-limiting step in these reactions is often the enolate ion formation, and that condensation and the subsequent dehydration reaction occur in rapid succession. These α-β unsaturated ketones and aldehydes are known to those skilled in the art to be quite reactive and susceptible to further consecutive, non-selective condensation, cyclization, and Michael-type addition reactions with the starting ketones and aldehydes, as well as themselves and other ketonic and aldehydic by-products. See, for example, H. O. House, Modern Synthetic Reactions, 2nd. Ed., 1972 pp. 595-599, 629-640.
Thus, in the base-catalyzed crossed condensation of an aldehyde of Formula I, possessing at least one hydrogen atom alpha to the carbonyl, with a ketone of Formula II, to form a desired β-hydroxy-ketone or α-β unsaturated ketone of Formulae III or IV, three parallel reaction pathways are known to compete: In general, R2, R1, R3, and R4 represent hydrogen or a C1 to C10 organic radical.
One skilled in the art would expect a broad range of products from these reactions. The further condensation of the α-β unsaturated ketones with the ketone of Formula II, or with the aldehyde of Formula I, or with other ketonic and aldehydic species, leads to many by-products and can represent significant yield losses as well as necessitate complicated and expensive purification schemes for the commercial production of high purity α,β-unsaturated ketones and saturated ketones. For example, in the preparation of methyl amyl ketone via the crossed condensation of n-butyraldehyde with acetone, the self-condensation of n-butyraldehyde to form 2-ethyl-2-hexenal is a particularly troublesome by-product. Its hydrogenated form, 2-ethylhexanal, boils less than 10° C. apart from 2-heptanone, and is therefore difficult to separate economically from 2-heptanone by distillation. It would clearly be an advance in the art to minimize formation of these unwanted aldehyde self-condensation by-products that are afterward difficult to remove from the reaction mixture.
One method of preventing unwanted further condensation side products in aldol condensation reactions is to quickly hydrogenate the α,β-unsaturated ketones. This can be accomplished in situ or in a separate hydrogenation step.
The production of higher molecular weight ketones using aldol condensations and catalytic hydrogenations can be carried out either by a multi-step process or a one-step process. A multi-step process uses sequentially discrete steps in two or three separate reactors. In a one-step process the reactions are carried out simultaneously in one reactor.
When ketones are synthesized by a multi-step process, using sequentially discrete steps, the aldol reaction occurs first, which is then followed by dehydration, and by subsequent hydrogenation. Each step is independent of the others, and the process often requires difficult separation techniques between steps. For example, U.S. Pat. No. 5,583,263 describes a multi-step process for the coproduction of methyl amyl ketone and methyl isobutyl ketone. In this process, dimethyl ketone is reacted with n-butyraldehyde using a fixed-bed basic ion exchange cross-aldol condensation catalyst to form a β-hydroxy ketone mixture. The product is then dehydrated to form an olefinic ketone using a catalytic quantity of an acidic substance, such as H2SO4, NaHSO4, or a sulfonic acid resin. The resulting α,β-unsaturated ketone is then hydrogenated using a solid phase hydrogenation catalyst to produce the desired amyl ketone. Three discrete steps are required, with costly separations between the steps. There is no acknowledgment that by-products other than methyl isobutyl ketone are produced, nor is there any suggestion how one might avoid impurities such as 2-ethylhexaldehyde and high boiling by-products that result from unwanted side reactions. On the basis of a comparative example, the authors conclude that commercial coproduction of methyl isobutyl ketone and methyl amyl ketone is impractical in one-step processes employing ordinary catalyst systems.
When ketones are produced in a one-step process, the aldol reaction, dehydration, and hydrogenation occur simultaneously in one reactor. Such one-step processes can be either batch or continuous processes.
In a one-step batch process, the reactions are carried out simultaneously in one reactor, and there is neither inflow nor outflow of reactants or products while the reaction is being carried out. In a one-step continuous process, the reactions are carried out simultaneously in one reactor, and reactants flow in and the products flow out while the reaction is being carried out. While the hydrogenation reaction is typically heterogeneously catalyzed, the aldol condensation can be either heterogeneously or homogeneously catalyzed in a one-step process.
For example, U.S. Pat. No. 2,499,172 (the '172 patent) describes a one-step batch process for the conversion of low-boiling ketones to high boiling ketones. Higher boiling ketones, such as methyl isobutyl ketone, are produced when lower boiling ketones, such as acetone and ethyl methyl ketone, are treated with hydrogen in the presence of a liquid alkaline condensation catalyst and a solid hydrogenation catalyst. The liquid alkaline condensation catalyst can be ammonia; amines, such as isopropylamine, diisopropylamine, trimethylamine, furfurylamine, difurfurylamine, and aniline; alkali-metal hydroxides; alkaline-earth-metal oxides and hydroxides; and alkali-metal salts of weak acids, such as sodium borate, carbonate, acetate and phosphates. The solid hydrogenation catalyst can contain palladium, for example 5% Pd/C.
The examples of the '172 patent describe a one-step batch process for the self-condensation of ketones. In general, self-aldol condensations of ketones lead to only one product. For example, the self-aldol condensation and hydrogenation product of dimethylketone is methyl isobutyl ketone. However, crossed aldol condensations—between ketones and aldehydes—lead to mixtures of products. For example, the crossed aldol condensation and hydrogenaton products of dimethylketone and n-butyraldehye are methyl amyl ketone, methyl isobutyl ketone, and 2-ethylhexaldehyde. We have found that when the one-step batch process described in the '172 patent is applied to the crossed aldol condensation of acetone and n-butyraldehdye, as seen in Example 1 (Comparative) of the present application, a large amount of high-boiling material is produced. As a result, the selectivity of n-butyraldehyde to methyl amyl ketone is poor. A further disadvantage of batch processes in general is that they often require large reaction apparatuses and storage tanks, because their capacity relative to the reaction volume is very small. Other drawbacks include high energy consumption and operator involvement, and high conversion costs.
The '172 patent advises that the process described in that patent may be carried out by passing the reactant mixture through a stationary bed of pelleted or supported catalysts, enclosed in a reaction vessel of suitable design. This suggests a fixed-bed plug-flow reactor process, such as that described in U.S. Pat. No. 5,324,871 for the hydrogenation of fatty acids and fatty acid esters to fatty alcohols, where the reactants are pumped straight through the catalyst bed and continually consumed as they flow down the length of a reactor, such as a tubular reactor. A fixed-bed reactor, sometimes called a packed-bed reactor, is typically a tubular reactor that is packed with solid catalyst particles.
When a continuous, fixed-bed plug-flow concept is applied to the crossed aldol condensation of acetone and n-butyraldehyde without recycle, as seen in Example 2 (Comparative) of the present application, a large amount of 2-ethylhexaldehyde by-product is produced, the result of the self-aldol condensation of n-butyraldehyde. The selectivity of n-butyraldehyde to methyl amyl ketone is thus very low, only 38%. While the use of a continuous plug-flow fixed-bed catalyst helps eliminate some of the disadvantages of a one-step batch process, such as the difficult catalyst recovery operations typical of a slurry process, we have not found this alternative to improve conversion or selectivity in crossed aldol condensation reactions. The main by-product of the one-step batch process, unknown high-boilers, can be easily separated from methyl amyl ketone. However, the main by-product of the continuous plug-flow fixed-bed catalyst process, 2-ethylhexaldehyde, cannot be easily separated from the methyl amyl ketone by distillation.
There remains a need for an improved process for producing higher molecular weight ketones having a higher yield and greater selectivity for the target product, which minimizes the amounts of unwanted by-products that are afterward difficult to remove from the reaction mixture.